Method for introducing a 21-hydroxy group into 17-oxygenated steroids



United States Patent METHOD FOR INTRODUCING A 21-HYDROXY GROUP INTO 17-0XYGENATED STEROIDS Percy L. Julian, Maywood, and Edwin W. Meyer, Isabelle Ryden, and William J. Karpel, Chicago, 111., assignors to The Glidden Company, Cleveland, Qhlma corporation of Ohio i No Drawing. Application February 8, 1950,

Serial N 143,146

22 Claims; (Cl. 260-23955) The present invention relates to a method for introducing a ZI-hydroxy group into l7-oxygenated pregnenes andpregnanes, and particularly relates to a method for preparing 2 1 -hydroxy-20-keto-17-oxygenated pregn enes and pregnanes.

Practically all of the known methods for preparing steroids having the group I involve the reaction of osmium tetroxide with compounds containing the grouping II. This gives rise to substances having the grouping III, which must then be oxidizedwith CH III c -OH KCECH I H;

(VII) 2,816,108 Patented Dec. I0, 1957 ice 7 (VIII); 7 (IX) Ih mu t p y of steps. and he e io s ca nvo ved in difficult reactions make it greatly desirable to obtain a simpler process for obtaining compounds bearing the grouping I. Thus, for example, large quantities of liquid ammonia and explosive potassium are involved in the transformation from VI to VII. Also greatest care must be exercised in the partial catalytic hydrogenation of VII to VIII.

Still a further disadvantage of the procedures outlined above'resides in the necessitous preparation, as starting material, of compounds containing either the system X or XI, both of which are difficult to obtain except in very meager yields.

CHZOR C /=O O Recently great attention has been directed to 3-keto- A -compounds containing in addition the grouping I, because of the discovery that Kendalls Compound E of the- Formula Ia represents the first therapeutic agent found that definitely alleviates the pains and accompanying symptoms of rheumatoid arthritis. It therefore becomes of universal interest to seek methods which may simplify the preparation of Compound E and related substances, spare precious raw material and make them available at reduced costs.

CHQOH Kendalls Compound E It is, therefore, an object of the, present invention to.

provide a simple method useful forpreparing substances bearing the grouping I and termed l7a-hydroxy-corticosteroids.

A further object of the invention is to prepare. these 17 -hydroxy steroids from more readily obtainable and cheaper starting materials than. those used, formerly.

' Another object is to providea method for introducing a Zl-hydroxy group into 20-keto-pregnenes and pregnanes.

An additional object is to provide av method for prepan injgpregnenes and pregnanes, having an hydroxy group. in the 2l-position, a keto. or hydroxy group in the 2 0.-p.osit i on and. which are oxygenated at the 17 -position.

Still another object is to provide a, process useful for prepitfiing pregnenes andrjprgnanes, bearing the group; mg, i

Other objects will be apparent from the following deseription.

It has been found that the 17a-hydroxy steroids of the type of Kendalls Compound E and Reichsteins Compound S may be obtained from readily available 17-acetyl steroids. The starting materials for this type of synthesis are compounds containing the grouping XII, namely, 17- acetyl-l6,17-dehydrosteroids. The compounds containing the grouping XII are readily converted into the corresponding 16,17a-Xid0 compounds containing the grouping XIII by treatment with perbenzoic acid. Where the initial starting materials are 5,16 pregnadienes, such as may be obtained by degradation of the side chain of over, protection of the -keto group by cyclic ethylene kctal formation, such as has been described in copending application Serial No. 108,658, filed August 4, 1949, followed by reduction with lithium aluminum hydride and acid hydrolysis, leads to compounds containing the structure XVIII. Another method of introducing this structure is to treat the compounds possessing the structure XVI with HBr to open up the oxide ring and form the structure XIX, and to then simply treat with standard Raney nickel in alcohol to form XVIII. Compounds of the structure XVIII are represented by both Kendalls Compound E and Reichsteins Compound S, which have recently been demonstrated to be therapeutically important steroids.

(3H3 CH; (lift, I C=O JJ=O C=O \f' \j' I I HBr Br Br,

(XII) (XIII) (XIV) (XV) t! 0K IIH OAcyI CH OH (i=0 lC= 11+ 0H --0H LiAiH with 0H intermediate ketal formation LiAlH;

(XVIII) (XVI) (XVII) Standaik l HBr Raney Nickel\ Hydrolysis CHzOAcyl (XIX) Indicates epimers.

in the 16,17-oxido compound, the procedure described in co-pending application Serial No. 109,808, filed August 11, 1949, may be employed. In the case of 16-pregnenes, however, such as may be obtained from sarsasapogenin, simple treatment of the pregnene with perbenzoic acid in a manner well known in the art is suflicient.

We have now found that oxido compounds containing the grouping XIII, on treatment with hydrobromic acid, suffer rupture of the oxido ring to produce 16-bromo-17ahydroxy compounds containing the grouping XIV. On treatment of structure XIV with bromine in an appropriate solvent, compounds containing the structure XV result. On treatment of XV with a metallic salt of a carboxylic acid, such as potassium or sodium acetate, formate, benzoate, etc.' in acetone, acetic acid or other suitable solvent, the 21-bromo group is replaced by an acyloXy group and the oxido structure is regenerated, resulting in compounds containing the structure XVI.

The attainment of structure XVI is a most novel and far-reaching development in the steroid field, for a relatively simple and inexpensive procedure has herewith been developed for introduction of the ketol side chain and the l7u-hydroxy group into steroids. Thus, treatment of compounds containing the grouping XVI, namely, that of a 21-acyloxy-16,17a-oxido structure, with lithium aluminum hydride, such as isdescribed in co-pending application Serial No. 93,638, filed May 16, 1949, leads smoothly to 17a,20,21-tr'ihydroxy steroids (XVII), which compounds are of extreme therapeutic significance. More- Thus, a novel and economical method has been achieved for the preparation of 17a-hydroxy steroids containing the 20,21-ketol side chain. Likewise a novel and relatively inexpensive method has been achieved for obtaining compounds containing the 17ahydr0Xy group as well as hydroxyl groups at positions 20,21.

In a specific illustration of this procedure, such as would be achieved in starting with 5,16-pregnadiene-3fi-ol-20- one acetate of the Formula XX, the bromo compound corresponding to XV above would have the structure represented by XXI. Naturally such a compound, before treatment with potassium acetate in acetone to produce compounds containing the structure corresponding to XVI must be dehalogenated at positions 5 and 6 of the steroid nucleus. This is accomplished by treatment with sodium iodide and leaves compounds CH1 CH Br OH O IT i A00 A00- 1 (XX) r (XXI) of. h t ctu e r p e y QHLs QQQ-Qg fiiisfih:

(XXII) (XXIII) The following examples will serve to illustrate the invention.

EXAMPLE I' The preparation 0 a. tetrabromide from 16;1i7'-0xid0-5- pregnenedfl-ol-ZO-On acetate I A solution of one gram of 16,lfla oxido wpregnenolone acetate in ml. o f'acetic acidwas treatedwith a s olu; tion of 0.430 g. of brominein 4.30 ml, of, acetic aeid at room temperature. After the bromine color had all dis; appeared, 1.5 ml. of HBr. in acetic acid and. 10ml, of. carbon tetrachloride was added and the mixture was allowed. to stand at room temperaturefor one-half hour. Amadditional 0.430 g. of bromine. in 4,30 ml. of acetic acid was then added. After, standing for 1 hours at room temperature, the bromine color had, disappeared. The carbon tetraehloride was removed in vacup and the remaining acetic acid solution was poured into water. The crystalline precipitate was filtered, Washed well with water and air dried. 1.79 g., M. P; 1 45 1 47 doc.

EXAMPLE In Preparation r -a do rpr s rne-fisZldWkZQ- diacetate The tetrabrornide from Example I was dissolvedpin 2.5 m1. of benzene and a,solution 'of 4. 0 g. of sodiurn iodide in. 25. ml. of ethanol was added; This mixture was allowed to stand a o em a ure or ZQhwraand then poured into a large volumeof ether and water. The ether layer was washed withdilute sodium thi'osulfate and water, dried. and concentrated in vacuo to a 'tarrsolid r du The total c e rq uct as iss e n. ml. of acetone and 3.00 g. of freshly fused; potassium acetatewas fid- T e xtur as rsfluxedifq hree hours, t acetone as r qy d. y. i llat aa a th residue was diluted with water and extractedwith ether, The ether layer was washed with waterto neutrality,

dried and concentrated; to dryness. Thefsolid residue EXAMPLE III Preparation of 21 -benzoxy-16,l 7-0xido5 pregnene j'fiwql- ZO-one acetate A solution of 2.14 g. of the tetrabromide of 16,170:-

oxide-pregnenolone, prepared as in Example I, in 30 ml.

was removed by distillation and, the residue was diluted with water and extracted with ether. The ether layer was washed with water to neutrality, dried and concentratedto dryness. The solid residue wascry stallized from chloroform-methanol. 710 mg., M. P. 189-190, softens 180. AnaL: Calc. for C H O C=73.l4, H-=7.3 6. Found; C= 72.94, H-=7;.57.

EXAMPLE IV The bromination of 16,1Z-oxidoJ-pregnerte-31301400112 in,ace tic acid.

A solution of' one gram of 16,17 -oxido-pregnenoIone in 10 ml. ofacetic acid was treated with0. 485 g. of bromine in 4:85 ml. ofjaeeticacid at room temperature. After the bromine color had all disappeared; 15ml. of 30% HBr inacetic acidand- 15ml. or; carbon tetrachloride were added. A precipitate appears which goes back into solution on standing! Aftero ne-h alf hour at room ternperature an additional 0.485 g. of bromine in 4, cc. of acetic acid was added; After standing for one hour at roon' temperature, the bromineeqlor and disappeared; The carhon tetrachloride was removed in vacuo and the acetic acid solution was'poured into water. The crystalline precipitate was filtered, Washed well with water and air dried. 2.14 g., M. P. -147 dec. There was no depression in melting point on admixture with the product from Example I; therefore, acetylation at position 3 has taken placein acetic acid in the presenceof HBr. The product whentreated asin Example II yields 1;6,17'- oxido -5+pregnene-3fi,2lrdio1-20-one diacetate, or whentreated as inExampleIII, 21-benzoxy-16,17-oxido 5 .-pregnene-3 3-ol.-20:-one acetate is obtained.

EXAMPLE V Treatment of 16, 1 7-oxido:pregnane-3-0[JO- ue. acetate To.as olution of 1 gram of 1 6,17-oxido-pregnane-3-oh 20 oneaceta te in 10 ml, of acetic acid is added 1.5 ml of 30%,. I-IBr. in acetic acid and 15 of fl fbon tetrachlo: ride. After one-half hour at room temperature there is added 0.430 g. of bromine in 4.30 ml. of acetic acid The mixture .is allowed to stand at room temperature until the bromine color disappears. The carbon tetrachloride is then. removed invacuoand theacetic acid solution poured into water, the precipitate filtered, washed well with water and dried. The crude dibromideis then taken up in acetone and 3.0 g. of freshly fused potassium acetate added and themixturerefluxed for three hours. The reaction mixture is then worked up as in Example II.

EXAMPLE VI 1,6,1 7,-oicidh-5-piregnene-3d2 l-diol-ZO-one 21-m0n0acetate A solution of 10.0 g, of 16,17,0xido-5-pregnene-3B-ol- 20-one acetate in 100 ml. of acetic acid and 100 m1. of carbon tetrachloride, chilled to 18, was treated with a solution of4.3 g. of bromine in 30 ml. of carbon tetrachloride. Upon complete decolorization, there was added 1 5 ml. of a 32% solution of hydrobromic acid in acetic acid. After the solution had stood for ten minutes at room temperature, a second molar equivalent of bromine, 43 g. in 30 ml. of carbon tetrachloride, was added portionwise at room temperature with stirring during a forty-minute period. The reaction mixture was allowed to stand for an additional fifteen minutes and then evaporated in vacuo with a minimum of heating to remove the carbon tetrachloride. The remaining suspension was poured into waten'filtered and the separated solid washed with water and dried at 40=. The solid 17.9 g., was dissolved in 7-5 ml. of benzene and 175 ml. of methanol and after the addition of-5.2 g. of hydrogen bromide in 15 ml. of methanol, the solution was allowed to. stand at room eammate 9? !.h. e herea ex r t of t reaction mixture which had been diluted with water was washed with water, dried, concentrated to 20 m1. and diluted with 155 ml. of benzene. After the addition of a solution of 36.5 g. of sodium iodide in 175 ml. of absolute ethanol, the mixture was allowed to stand at room temperature for twenty-two hours. It was then diluted well with water and extracted with ether. The ether extract was washed with 3% sodium thiosulfate solution and then with water. The cream-colored residue (14.5 g.) remaining after removal of ether in vacuo was dissolved in 300 ml. of acetone containing 42 g. of freshly-fused potassium acetate. .The mixture was refluxed for four and one-half hours, then concentrated to a small volume, diluted with water and extracted with ether. The waterwashed and dried ethereal solution gave upon concentration to a small volume, 5.5 g. of 16,17-oxido-5-preg nene-3,6,21,-diol-20-one 21 monoacetate melting at 180- 188. A reslurry of the monoacetate in ether yielded 5.0 g. of material melting at 188-190". Further recrystallization from acetone gave needles melting at 190-192. .(a) 2 +14.99 (8.7 mg. made up to 2 ml. with chlorofOI'm, d +0.065, l, 1 dm.)- Anal.: Calcd. for C23H32O5I C, 71.11; H, 8.30. Found: C, 70.86; H, 8.33.

EXAMPLE VII 1 6 ,1 7-0xido-4-pregnene-21-0l-3,20-di0ne acetate A solution of 6.5 g. of aluminum isopropoxide in 60 ml. of toluene was added dropwise during five minutes to a refluxing solution of 15.0 g. of 16,17-oxido-5-pregnene- 3 8,21-diol-20-one 21-monoacetate in 600 ml. of toluene. The mixture was refluxed for an additional one-half hour and after the addition of 3 ml. of acetic acid in 20 ml. of toluene, it was steam distilled. The crystalline residue was dissolved in ether and washed with 1% sulfuric acid, 1% sodium hydroxide solution and then with water to neutrality. Addition of petroleum ether (B. P. 35-60) to the dried and concentrated (60 ml.) ethereal solution gave 9.0 g. of 16,17-oxido-4-pregnene-21-ol-3,20-dione acetate in clusters of needles melting at 168-1,70. From the mother liquor there was secured an additional 1.5 g. of material melting at 165-168". Several recrystallizations from ether-petroleum ether (B. P. 35-60) gave prisms melting at 170-l72. (a) +166.8 (7.1 mg. made up to 2 ml. with chloroform, oc +0.592, l, 1 dm.). Anal.: Calcd. for C H O C, 71.48; H, 7.82. Found: C, 71.82; H, 8.23.

EXAMPLE VIII 7a-lzydroxy-1 I -desxyc0rticosterone acetate A solution of 20 ml. of 32% hydrobromic acid in acetic acid was added to a solution of 20.0 g. of 16,17-oxido-4- pregnene-Zl-ol-3,20-dione acetate in 100 ml. of acetic acid and chilled to 15-18. The solution, red-brown in color, was held for fifteen minutes at room temperature and then cooled to 18 for an additional fifteen minutes. The crystalline bromohydrin (23.5 g.) which separated within two to three minutes on chilling was filtered, washed well with alcohol-free ether and dried in vacuo at 40. A sample of the bromohydrin when recrystallized from benzene-ether formed needles melting at 177-178, dec. Anal.: Calcd. for C H O Br: C, 59.10; H, 6.73. Found: C, 59.26; H., 7.05.

A solution of 23.5 g. of the bromohydrin in 750 ml. of ethanol was stirred and refluxed with 98 g. of Raney nickel 1 for five hours, and then filtered while hot through a bed of filter-aid. The pale yellow filtrate was concentrated in vacuo to a slurry of needle-like crystals and chilled. The white solid was filtered and washed with 100 ml. of cold acetone. After drying at 65, there was obtained 12.5 g. of l7m-hydroxy-ll-desoxycorticosterone Reactions of Hydrogen: Adkins, Univ. of Wisconsin Press, Madison, Wisconsin (1937).

V 8 acetate melting at 226-231. Recrystallization from acetone raised the melting point to 235-238" (sinters 230). This material showed no depression in melting point when admixed with a sample of the acetate of 17a.- hydroxy-ll-desoxycorticosterone isolated from a natural source. (a) +1l4 (11.2 mg. made up to 5 ml. with acetone, u +0.255, l, 1 dm.). Anal.: Calcd. for C H O C, 71.11; H, 8.30. Found: C, 70.94; H, 8.28.

An additional small crop of crude material was recovered from the original mother liquor. The mother liquor was diluted with water, extracted with ether and washed with 1% sodium hydroxide solution and with water. The dried ethereal solution was concentrated to a gummy residue which upon recrystallization from acetone gave 880 mg. of material melting at 195-220.

EXAMPLE IX 1 7a-hydr0xy-1I-desoxycorticosterone A solution of 500 mg. of 17a-hydroxy-1l-desoxycorticosterone acetate in ml. of methanol containing 500 mg. of potassium bicarbonate in 10 ml. of water was allowed to stand at room temperature for twenty-four hours. It was then diluted with saline solution and extracted with freshly distilled ether. The ether solution was washed with water to neutrality, dried and concentrated to 10 ml. After chilling, the separated solid was filtered and washed with cold ether. There resulted 290 mg. of fine, glistening plates melting at ZOO-208.

Recrystallization of this material from acetone raised the melting point to 207-208".

Many variations may be carried out in this type of preparation, as should be obvious to one experienced in the art. Thus, compounds of the type XXIII may be converted into 20-cyclic ethylene ketals before lithium aluminum hydride reduction. Hydrolysis after lithium hydride treatment will then lead to l7a,21-hydroxy-20- keto compounds. Where a 16,17-oxido-pregnane is the starting material, it is, of course, not necessary to treat with sodium iodide, since removal of bromine from a 5,6 dibromide is not necessary, and the 16,17-oxido compound may be treated directly with HBr and bromine and the resulting dibromide treated with potassium acetate in acetone or other solvent. Replacement of the 21- bromine atom of the saturated compound with iodine may, of course, be resorted to if desired, and the resulting 21-iodo compound treated with potassium salt.

Also it is not essential to start with acetylated 3-hydroxy compounds where such are used. In the case of unsaturated oxido compounds, however, bromination in acetic acidis convenient for the bromination and under these conditions acetylation occurs. Other esters such as the formate, benzoate, etc. may be employed as starting material if the acetate is undesirable and if the -OH group is to be retained unesterified, the bromination may be carried out under non-acetylating conditions. However, it is preferred to start with acylated 3-hydroxy compounds and then to restore the 3-OH group after introduction of the 21-halo group and before formation of the 2l-acyloxy group. This may be done by subjecting the 3-acyloxy-21-halo compound to a mild hydrolysis with HBr in methyl alcohol as shown in Example VI. Where the compounds also contain a 5,6 dibromo grouping, the hydrolysis may take place either before or after removal of the 5,6 bromine atoms and replacement of the 21-bromine atom with iodine. Likewise, other salts than the acetate and benzoate, such as the propionate and the like, may be employed for replacement of the 21- halogen atom and for restoration of the 16,17-oxido group.

Also many other pregnenes and pregnanes may be used in the present invention. Thus, pregnenes and pregnanes possessing an oxygenated function, such as keto,

1 hydroxyand acyloxy groups, at the 11 or 12 position of the nucleus may be treated to form the 21-hydroxy-17- o y en ted. erivat v s- Sta tin omp un o yg n in ineQmay. for examnl r e p e d from b cid such as desoxycholic acid by degradation of the side chain and formation of a A double bond, by known methods, such as that of Butenandt et al., Ber 71, 1487 (1938 72, 182 (19,39). Wherean lleoxygenated compound is desired, the transposition of the, l2-oxy'genated to the ll-oxygenated compound may be eflected by any of the known methods, preferably before degradation of the side chain. However, the transposition may be carried out after the degradation of the side chain or after the reactions here described have been carried out.

It is thus seen that a process is provided for producing 17a-hydroxy-21-hydroxy pregnenes and pregnanes from steroids which do not possess these groupings without the use of expensive and/ or dangerous reagents. Since the starting materials are much more readily available than the natural substances containing such groupings, this invention assumes particular significance in view of the recent widespread interest in such hydroxylated steroids in the treatment of rheumatoid arthritis.

Having described the invention, what is claimed is:

1. The process which comprises subjecting steroids selected from the class consisting of 16-bromo-17a-hydroxy- 20-keto-21-iodo and 16-bromo-17u-hydroxy-20 keto-Zlbromo pregnenes and pregnanes to the action of a metallic salt of a carboxylic acid whereby the 21-halogen atom is replaced by an acyloxy group and a 16,17-oxido group is formed.

2. The process which comprises subjecting steroids selected from the class consisting of 16-bromo-17u-hydroxy- 20-keto-2l-iodo and 16-bromo-17a-hydroXy-20-keto 21- bromo pregnenes and pregnanes to the action of an alkali metal salt of a carboxylic acid whereby the 21-halogen atom is replaced by an acyloxy group and a 16,17-oxido group is formed.

3. The process which comprises subjecting steroids selected from the class consisting of 16-bromo-17a.-hydroxy- 20-keto-21-iodo and 16-bromo-17a-hydroxy-2O keto-21- bromo pregnenes and pregnanes to the action of a potassium salt of a carboxylic acid whereby the 21-halogen atom is replaced by an acyloxy group and a 16,17-oxido group is formed.

4. The process of claim 1 in which the salt is potassium acetate.

5. The process of claim 1 in which the salt is potassium benzoate.

6. The process which comprises subjecting a 16-bromo- 17a-hydroxy-20-keto-2l-iodo pregnene to the action of a metallic salt of a carboxylic acid whereby the 21-iodine atom is replaced by an acyloxy group and a 16,17-oxido group is formed.

7. The process which comprises subjecting a 16-bromo- 17a-hydroxy-20-keto-2l-bromo pregnane to the action of a metallic salt of a carboxylic acid whereby the 21- bromine atom is replaced by an acyloxy group and a 16,17-oxido group is formed.

8. The process which comprises treating a 16,170;- oxido-S-pregnene-ZO-one with bromine to saturate the nuclear double bond, treating the brominated product with HBr to open up to the oxido ring and then with bromine to introduce a ZI-bromo group, treating the resulting tetrabromide with suflicient sodium iodide to restore the nuclear double bond and to replace the 21- bromine atom with iodine, and then subjecting the resulting 21-iodo compound to the action of a metallic salt of a carboxylic acid whereby the 21-iodine atom is replaced by an acyloxy group and the 16,17-oxido group is restored.

9. The process of claim 8 in which the salt is a salt of an alkali metal.

10. The process of claim 8 in which the salt is potassium acetate.

11. The process of claim 8 in which the salt is potassium benzoate.

12. The process which comprises treating a 5,6,16-tri- 10 bromod'lurhydroxyao-keto pregnane with bromine to introduce a. bromine atom in the 21-position, removing the5,6-,bromine atoms, 'and replacing the 21-bromine with iodine by treatment with sodium iodide, and then treating with a metallic salt, of a carboxylic acid to form a 16,170:- oxido group and to replace the 2l-iodine atom with an acyloxy group.

13. The process which comprises treating a 16,17aoxido-Zl-keto pregnane with HBr to open up the oxido ring and then with bromine to introduce a 21-bromo group, and subjecting the resulting dibrornide to the action of a metallic salt of a carboxylic acid whereby the 2l-bromine atom is replaced by an acyloxy group and the 16,17a-oxido group is restored.

14. The process which comprises subjecting steroids selected from the class consisting of 16-bromo-l7a-hydr-oxy-ZO-keto-Zl-iodo and 16-bromo-17a-hydroxy-20- keto-2l-bromo pregnenes and pregnanes to the action of a metallic salt of a carboxylic acid whereby the 2l-halogen atom is replaced by an acyloxy group and a 16,170t-0Xid0 group is formed, and reducing the 16,17-oXido group thus formed with lithium aluminum hydride.

15 The process of claim 14 in which the ZO-keto group is protected during the reduction with lithium aluminum hydride by conversion to a cyclic ketal.

16. The process which comprises treating a steroid vicinal bromohydrin with Raney nickel in sufiicient amount to replace the bromo group adjacent to the hydroxyl group with hydrogen.

17. The process which comprises treating a 3-acetoxy- 5,6-dibIOmO-16,170t-OXidO-20-kt0 pregnane with HBr to open up the oxide ring, treating the resulting 3-acetoxy- 5,6,16-tribromo-17a-hydroxy-20-keto pregnane with bromine to form a 3acetoXy-5,6,16,21-tetrabromo-17ot-hydroxy-20-keto pregnane, then treating with HBr in alcohol and with sodium iodide to hydrolyze the 3-acetoxy group to a hydroxy group, to remove the 5,6-bromine atoms and to replace the 2l-bromine atom with iodine, treating the resulting 3,l7tx-dihydroxy-l6-bromo-2l-iodo-A -pregnene with a metallic salt of a carboxylic acid whereby the 21- iodine atom is replaced by an acyloxy group and the 16,17a-oxido group is restored, subjecting the resulting 3 hydroxy -16,17a-oxido-20-keto-2l-acyloXy-A -pregnene to an Oppenauer oxidation to form a 3,20-dil(eto-16,l7aoxide-2l-acyloxy-A -pregnene, then opening up the 16,17rx-0Xid0 group with HBr, and then treating with Raney nickel to replace the 16-bromine atom with hydrogen.

18. The process which comprises subjecting steroids selected from the class consisting of 16-bromo-17u-hydroxy-20-keto-21-iodo and 16-bromo-17a-hydroXy-20- keto-Zl-bromo pregnenes and pregnanes to the action of a metallic salt of a carboxylic acid whereby the 21-halogen atom is replaced by an acyloxy group and a 16,17-oxido group is formed, thereafter opening up the oxide group by treatment with HBr, and then treating with Raney nickel to replace the l6-bromine atom thus introduced with hydrogen.

19. The process which comprises subjecting 3-acyloxyl7a-hydroxy-20-keto-2l-iodo-5-pregnene to the action of a metallic salt of a lower hydrocarbon carboxylic acid, whereby the 21-iodo group is replaced by an acyloxy group and a 16,17-oxido group is formed.

20. The process which comprises treating 3-acyloxy- 16,17u-oxido-20-keto-S-pregnene with bromine to saturate the nuclear double bond, treating the brominated product with HBr to open up the oxide group and then with bromine to introduce a 2l-bromo group, treating the resulting tetrabromide with sufiicient sodium iodide to restore the nuclear double bond and to replace the 21- bromine atom with iodine, and then subjecting the 21 iodo compound to the action of a metallic salt of a lower hydrocarbon carboxylic acid whereby the 21-iodine atom is replaced by an acyloxy group and the 16,17-oxido group is restored.

.21. The process which comprises treating 3-acyloxy- 5,6,IG-tribromo-17u-hydrOXy-ZO-keto-pregnane with bromine to introduce a 21-bromo group, treating the tetrabromide with sufficient sodium iodide to remove the 5,6-brorno groups and to replace the 21-bromine atom with iodine, and then treating with a metallic salt of a lower hydrocarbon carboxylic acid to replace the 21-iodo group with an acyloxy group and to form a 16,17-oxid0 group.

12 r 22: The 3-esters of 3,17a-dihyd'roxy-16-bromo-20-ket0- 21-iodo-5-pregnene with a lower hydrocarbon carboxylic acid. l

References Cited in the file of this patent Plattner: Helv. Chim. Acta 30, 395-402 (1947). Fieser et'aL: Natural Products Related to Phenanthrene, 3rd edition, pp. 407, 424-426 (1949). 

1. THE PROCESS WHICH COMPRISES SUBJECTING STEROIDS SELECTED FROM THE CLASS CONSISTING OF 16-BROMO-17A-HYDROXY20-KETO-21-IODO AND 16-BROMO-17A-HYDROXY-20- KETO-21BROMO PREGNENES AND PREGNANES TO THE ACTION OF A METALLIC SALT OF A CARBOXYLIC ACID WHEREBY THE 21-HALOGEN ATOM IS REPLACED BY AN ACYLOXY GROUP AND A 16,17-OXIDO GROUP IS FORMED. 